Estrogen Plays Surprise Role in Breast Cancer Treatment

TUESDAY Aug. 18, 2009 -- Researchers report that the paradoxical strategy of treating breast cancers that have become resistant to anti-estrogen therapies with estrogen actually shrank some tumors.

Not only that, but the estrogen made some of the tumors sensitive to anti-estrogen drugs once again.

The findings, reported in the Aug. 19 issue of the Journal of the American Medical Association, are preliminary, one expert cautioned.

"It's an interesting observation, but it needs to be expanded into a large trial," said Dr. Jay Brooks, chairman of hematology/oncology at Ochsner Health System in Baton Rouge, La. "There's probably something biologically going on here that we don't quite understand. The question is, can we translate this into really clinically meaningful responses?"

"The history of treating patients with estrogen goes back to the 1940s when physicians started to treat patients with advanced breast cancer with diethylstilbestrol or DES [a synthetic estrogen]," explained Dr. Matthew Ellis, a professor of medicine at Washington University School of Medicine, an oncologist with the Siteman Cancer Center in St. Louis and a co-author of the study. "The ancient literature is full of grainy photographs with lung metastases or local, advanced breast cancer or bone metastases getting better with this paradoxical treatment."

That treatment protocol was displaced by the anti-estrogen therapy tamoxifen in the 1970s. And tamoxifen is now being replaced by stronger anti-estrogen drugs known as aromatase inhibitors.

"These drugs are a little more effective than tamoxifen ... so now you have a large population of patients with advanced breast cancer who have experienced treatment often with both estrogen-lowering agents," Ellis said. "We hypothesized that some of these patients could go back to estrogen therapy, but at a lower dose than anything looked at before."

"Giving estrogen actually was a standard-of-care practice prior to tamoxifen approval, so this trial simply confirms previously known knowledge, that estrogen can be used to treat metastatic hormone-dependent breast cancer in postmenopausal women," said Dr. Ramona Swaby, an assistant professor of medical oncology at Fox Chase Cancer Center in Philadelphia.

To try to prove the point that lower doses of estrogen might work, 66 women with metastatic breast cancer and estrogen-receptor-positive tumors were randomized to receive either 6 milligrams or 30 milligrams of oral estradiol (estrogen) each day. All women had been treated previously with an aromatase inhibitor but their disease returned.

The two doses were similar in effectiveness, with tumors shrinking or not growing in about 30 percent of the women.

But those taking the higher dose had more negative side effects than those in the lower-dose group, as well as a poorer quality of life, making the lower dose the overall winner.

Meanwhile, the researchers also found that they could predict which tumors would respond based on results from positron emission tomography (PET) scans taken before and after the treatment. Tumors that glowed more brightly were much more likely to respond to the estrogen treatment, according to the study.

Some of the cancers later recurred, but about a third of these women then responded again to aromatase inhibitors.

Ellis also noted that 6 milligrams of estrogen costs only about $1 a day.

No one yet knows why this effect is happens to certain women.

"The endocrine system is a complicated system of feedback loops and, under normal circumstances, women experience wild changes in estrogen levels, depending on whether they're menstruating, pregnant or postmenopausal," Ellis explained. "All this is regulated in an exquisite way, which we actually understand fairly well. These results mean the feedback loops may be corrupted in some ways."

Brooks agreed that it's "counterintuitive."

"The estrogen receptor on a cancer cell is not a simple thing," he said. "Aromatase inhibitors may somehow allow the cells to reactivate certain [hormone] receptors [on the tumor] that may actually be different than they were to start with."

The researchers said they were planning further studies to see which group of women might benefit most from the protocol.

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